scholarly journals Endonuclease-induced DNA damage and cell death in oxidant injury to renal tubular epithelial cells.

1992 ◽  
Vol 90 (6) ◽  
pp. 2593-2597 ◽  
Author(s):  
N Ueda ◽  
S V Shah
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Epithelial Cells ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Oxidant Injury ◽  
Renal Tubular

scholarly journals Role of Ceramide Synthase in Oxidant Injury to Renal Tubular Epithelial Cells

2001 ◽  
Vol 12 (11) ◽  
pp. 2384-2391 ◽  
Author(s):  
NORISHI UEDA ◽  
SIMONE M. R. CAMARGO ◽  
XIAOMAN HONG ◽  
ALEXEI G. BASNAKIAN ◽  
PATRICK D. WALKER ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Epithelial Cells ◽  
Oxidant Stress ◽  
Ceramide Synthase ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Ceramide Generation

Abstract. Ceramide has been implicated to play an important role in the cell signaling pathway involved in apoptosis. Most studies that have used the apoptotic model of cellular injury have suggested that enhanced ceramide generation is the result of the breakdown of sphingomyelin by sphingomyelinases. However, the role of ceramide synthase in enhanced ceramide generation in response to oxidant stress has not been previously examined in any tissue. Hydrogen peroxide (H2O2) (1 mM) resulted in a rapid increase in ceramide generation (as measured by in vitro diacylglycerol kinase assay) in LLC-PK1 cells. The intracellular ceramide level was significantly increased at 5 min after exposure of cells to H2O2 and thereafter continuously increased up to 60 min. H2O2 also resulted in a rapid increase (within 5 min) in ceramide synthase activity (as measured by incorporation of [14C] from the labeled palmytoyl—CoA into dihydroceramide) in microsomes. In contrast, the exposure of cells to H2O2 did not result in any significant change in sphingomyelin content or acid or neutral sphingomyelinase activity. An increase in ceramide production induced by H2O2 preceded any evidence of DNA damage and cell death. The specific inhibitor of ceramide synthase, fumonisin B1 (50 μM), was able to suppress H2O2-induced ceramide generation and provided a marked protection against H2O2-induced DNA strand breaks, DNA fragmentation, and cell death. Taken together, these data provide the first evidence that H2O2 is a regulator of ceramide synthase rather than sphingomyelinases and that ceramide synthase—dependent ceramide generation plays a key role in DNA damage and cell death in oxidant stress to renal tubular epithelial cells.

Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells

2008 ◽  
Vol 294 (4) ◽  
pp. F777-F787 ◽  
Author(s):  
Cheng Yang ◽  
Varsha Kaushal ◽  
Sudhir V. Shah ◽  
Gur P. Kaushal
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Beclin 1 ◽  
Lag Phase ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Normal Cells ◽  
Life And Death ◽  
Renal Tubular ◽  
Induced Apoptosis

Autophagy has emerged as another major “programmed” mechanism to control life and death much like “programmed cell death” is for apoptosis in eukaryotes. We examined the expression of autophagic proteins and formation of autophagosomes during progression of cisplatin injury to renal tubular epithelial cells (RTEC). Autophagy was detected as early as 2–4 h after cisplatin exposure as indicated by induction of LC3-I, conversion of LC3-I to LC3-II protein, and upregulation of Beclin 1 and Atg5, essential markers of autophagy. The appearance of cisplatin-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in RTEC provided further evidence for autophagy. The autophagy inhibitor 3-methyladenine blocked punctated staining of autophagosomes. The staining of normal cells with acridine orange displayed green fluorescence with cytoplasmic and nuclear components in normal cells but displayed considerable red fluorescence in cisplatin-treated cells, suggesting formation of numerous acidic autophagolysosomal vacuoles. Autophagy inhibitors LY294002 or 3-methyladenine or wortmannin inhibited the formation of autophagosomes but induced apoptosis after 2–4 h of cisplatin treatment as indicated by caspase-3/7 and -6 activation, nuclear fragmentation, and cell death. This switch from autophagy to apoptosis by autophagic inhibitors further suggests that the preapoptotic lag phase after treatment with cisplatin is mediated by autophagy. At later stages of cisplatin injury, apoptosis was also found to be associated with autophagy, as autophagic inhibitors and inactivation of autophagy proteins Beclin 1 and Atg5 enhanced activation of caspases and apoptosis. Our results demonstrate that induction of autophagy mounts an adaptive response, suppresses cisplatin-induced apoptosis, and prolongs survival of RTEC.

scholarly journals Novel lnc RNA regulated by HIF-1 inhibits apoptotic cell death in the renal tubular epithelial cells under hypoxia

2017 ◽  
Vol 5 (8) ◽  
pp. e13203 ◽  
Author(s):  
Imari Mimura ◽  
Yosuke Hirakawa ◽  
Yasuharu Kanki ◽  
Natsuki Kushida ◽  
Ryo Nakaki ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular

Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells

2016 ◽  
Vol 292 ◽  
pp. 103-114 ◽  
Author(s):  
Katharina Krüger ◽  
Verena Ziegler ◽  
Christina Hartmann ◽  
Christian Henninger ◽  
Jürgen Thomale ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Dna Damage Response ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Damage Response ◽  
Renal Tubular

Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation

2005 ◽  
Vol 288 (2) ◽  
pp. F308-F314 ◽  
Author(s):  
Alexei G. Basnakian ◽  
Norishi Ueda ◽  
Xiaoman Hong ◽  
Valentin E. Galitovsky ◽  
Xiaoyan Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Ceramide Synthase ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Ceramide Level ◽  
Reoxygenation Injury ◽  
Renal Tubular ◽  
Ceramide Generation ◽  
Hypoxia Reoxygenation

Ceramide is known to play a role in the cell signaling pathway involved in apoptosis. Most studies suggest that enhanced ceramide generation is the result of hydrolysis of sphingomyelin by sphingomyelinases. However, the role of ceramide synthase in enhanced ceramide generation has not been previously examined in hypoxia-reoxygenation injury. In the present study, we demonstrated that 60-min hypoxia of rat renal tubular epithelial NRK-52E cells in a gas chamber with 95% N2-5% CO2 with glucose deprivation resulted in a significant increase in ceramide generation. The ceramide level further increased after reoxygenation for 60 min. Exposure of cells to hypoxia-reoxygenation resulted in a significant increase in ceramide synthase activity without any significant change in acid or neutral sphingomyelinase. The hypoxia-reoxygenation of NRK-52E cells was also associated with the release of endonuclease G (EndoG) from mitochondria to cytoplasm measured by Western blot analysis and endonuclease activity assay. It further led to the fragmentation of DNA and cell death. A specific inhibitor of ceramide synthase, fumonisin B1 (50 μM), suppressed hypoxia-reoxygenation-induced ceramide generation and provided protection against hypoxia-reoxygenation-induced EndoG release, DNA fragmentation, and cell death. Taken together, our data suggest that hypoxia-reoxygenation results in an activation of ceramide synthase rather than sphingomyelinase and that ceramide synthase-dependent ceramide generation is a key modulator of EndoG-mediated cytotoxicity in hypoxia-reoxygenation injury to renal tubular epithelial cells.

Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells

2015 ◽  
Vol 308 (6) ◽  
pp. F639-F649 ◽  
Author(s):  
Wei Jing Liu ◽  
Bi-Hua Xu ◽  
Lin Ye ◽  
Dong Liang ◽  
Hong-Luan Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Cathepsin B ◽  
Urinary Protein ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Urinary Proteins ◽  
Lysosomal Membrane Permeabilization ◽  
Lysosomal Dysfunction ◽  
Renal Tubular

Lysosomal membrane permeabilization (LMP) has been shown to cause the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol and initiate a cell death pathway. Whether proteinuria triggers LMP in renal tubular epithelial cells (TECs) to accelerate the progression of renal tubulointerstitial injury remains unclear. In the present study, we evaluated TEC injury as well as changes in lysosomal number, volume, activity, and membrane integrity after urinary protein overload in vivo and in vitro. Our results revealed that neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels were significantly increased in the urine of patients with minimal change nephrotic syndrome (MCNS) and the culture supernatant of HK-2 cells treated by urinary proteins extracted from MCNS patients. Urinary protein overload also induced apoptotic cell death in HK-2 cells. Importantly, we found that lysosomal volume and number were markedly increased in TECs of patients with MCNS and HK-2 cells overloaded with urinary proteins. However, lysosome function, as assessed by proteolytic degradation of DQ-ovalbumin and cathepsin-B and cathepsin-L activities, was decreased in HK-2 cells overloaded with urinary proteins. Furthermore, urinary protein overload led to a diffuse cytoplasmic immunostaining pattern of cathepsin-B and irregular immunostaining of lysosome-associated membrane protein-1, accompanying a reduction in intracellular acidic components, which could be improved by pretreatment with antioxidant. Taken together, our results indicate that overloading of urinary proteins caused LMP and lysosomal dysfunction at least partly via oxidative stress in TECs.

scholarly journals Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Bo Zhang ◽  
Xiang Chen ◽  
Feng Ru ◽  
Yu Gan ◽  
Bingsheng Li ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Epithelial Cells ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Hk2 Cells

AbstractRenal fibrosis is a common pathological process that occurs with diverse etiologies in chronic kidney disease. However, its regulatory mechanisms have not yet been fully elucidated. Ferroptosis is a form of non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. It is currently unknown whether ferroptosis is initiated during unilateral ureteral obstruction (UUO)-induced renal fibrosis and its role has not been determined. In this study, we demonstrated that ureteral obstruction induced ferroptosis in renal tubular epithelial cells (TECs) in vivo. The ferroptosis inhibitor liproxstatin-1 (Lip-1) reduced iron deposition, cell death, lipid peroxidation, and inhibited the downregulation of GPX4 expression induced by UUO, ultimately inhibiting ferroptosis in TECs. We found that Lip-1 significantly attenuated UUO-induced morphological and pathological changes and collagen deposition of renal fibrosis in mice. In addition, Lip-1 attenuated the expression of profibrotic factors in the UUO model. In vitro, we used RSL3 treatment and knocked down of GPX4 level by RNAi in HK2 cells to induce ferroptosis. Our results indicated HK2 cells secreted various profibrotic factors during ferroptosis. Lip-1 was able to inhibit ferroptosis and thereby inhibit the secretion of the profibrotic factors during the process. Incubation of kidney fibroblasts with culture medium from RSL3-induced HK2 cells promoted fibroblast proliferation and activation, whereas Lip-1 impeded the profibrotic effects. Our study found that Lip-1 may relieve renal fibrosis by inhibiting ferroptosis in TECs. Mechanistically, Lip-1 could reduce the activation of surrounding fibroblasts by inhibiting the paracrine of profibrotic factors in HK2 cells. Lip-1 may potentially be used as a therapeutic approach for the treatment of UUO-induced renal fibrosis.

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